U.S. Pat. No. 4,882,432 teaches ureas with high 5-HT1A receptor affinities. These compounds, as well as those disclosed in U.S. Pat. No. 4,797,489 are useful for the treatment of CNS disorders.
This invention relates to novel arylpiperidine and aryl-1,2,5,6-tetrahydropyridine amide derivatives which are agonists and antagonists of the 5HT1A receptor subtype. By virtue of their high binding affinity to the 5HT1A receptor, compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic, obsessive-compulsive disorder (OCD), sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer""s disease, Parkinson""s disease, obesity and migraine.
Compounds of the present invention are represented by the general formula (A), 
wherein:
R1 is alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl or heteroaryl; provided that the point of attachment is a carbon atoms;
R2 is hydrogen, alkyl or (CH2)R5;
R3 is hydrogen or alkyl;
X is hydrogen, halogen, perhaloalkyl, hydroxy, alkoxy, or perhaloalkoxy;
R4 is aryl or heteroaryl;
R5 is alkyl, alkenyl or alkynyl;
n is an integer from 1 to 3; and the dotted line is an optional double bond, or a pharmaceutical salt thereof.
In some preferred embodiments of the present invention R1 is cycloalkyl. In still other preferred embodiments of the present invention X is 4- or 5-fluoro and more preferably X is 5-fluoro. In other preferred embodiments of the present invention R4 is phenyl or pyridyl.
Alkyl, as used herein refers to straight or branched chain alkyl of 1 to 6 carbon atoms. In some preferred embodiments alkyl is straight chain alkyl of 1-5 carbon atoms and in some embodiments 1-4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. In some preferred embodiments, the alkyl group has from 1 to 5 carbon atoms. In some embodiments of the present invention the alkyl group may be substituted with one or more substituents.
Alkenyl, as used herein refers to straight or branched chain alkyl of 2 to 6 carbon atoms having at least one carbon-carbon double bond. Exemplary alkenyl groups include ethylene and propylene. In some embodiments of the present invention the alkenyl group may be substituted with one or more substituents.
Alkynyl, as used herein refers to straight or branched chain alkyl of 2 to 6 carbon atoms having at least one carbon-carbon triple bond. Exemplary alkenyl groups include ethynyl and propynyl. In some embodiments of the present invention the alkynyl group may be substituted with one or more substituents.
Cycloalkyl, as used herein refers to monocyclic alkyl group having from 3 to 8 carbons. Cycloalkyl groups may be substituted or unsubstituted. In some preferred embodiments of the present invention the cycloalkyl group may be substituted with one to three substituents. A preferred substitution of cycloalkyl is alkyl of 1 to 4 carbon atoms.
Aryl, as used herein refers to mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary aryl groups include phenyl and naphthyl. Aryl may be substituted with from one to three substituents. Heteroaryl, as used herein refers to 5 to 10 membered mono or bicyclic aromatic rings having from 1 to 3 heteroatoms selected from N, O and S. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazoly, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl and isoquinoly. Preferred heteroaryl groups include pyridyl, furyl and thienyl. Most preferred heteroaryls include 2-, 3- and 4-pyridyl, 2- and 3-furyl and 2- or 3-thienyl. Heteroaryls may also be substituted with from one to three substituents.
Halogen as used herein includes fluorine, chlorine, iodine and bromine.
Suitable substituents, unless otherwise noted, include halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino and aryl.
Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
The compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
Compounds of formula A and intermediates 4-(halo-2-methoxy-phenyl)-piperidines F or 4-(halo-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridines H of the present invention can be prepared by conventional methods by those skilled in the organic synthesis. For example, in Scheme I, metal-halogen exchange of an appropriately substituted aryl halide B with a base, such as butyllithium, forms a carboanion, and treatment of the resulting mixture with an N-protected-4-piperidone C affords a tertiary alcohol D. An example of the nitrogen protecting group (Rx)? of the 4-piperidone is benzyl, which can he removed by hydrogenation to afford amine G. Dehydration of G with an acid, such as sulfuric acid can provide the desired 4-(halo-2-methoxy-phenyl)-1,2,5,6-tetra-hydropyridine H. Dehydration of the tertiary alcohol D, removal of the nitrogen protecting group and hydrogenation of the double bond can afford 4-(halo-2-methoxy-phenyl)-piperidine F.
The des-halo intermediates 4-(2-methoxyphenyl)-piperidine F (Xxe2x95x90H) and 1,2,3,6-tetra hydro-4-(2-methoxyphenyl)-pyridine H (Xxe2x95x90H) are both known compounds and may be prepared by the following literature procedures:
Van Wijngaarden Ineke et al, J. Med. Chem., (1988), 31(10), 1934-1940.
Perregaard Jens et al., J. Med. Chem., (1995), 38(11), 1998-2008.
Modica Maria et al., J. Med. Chem., (1997), 40(4), 574-585.
Solyom Sandor et al., Heterocycles, (1995), 41(6), 1139-1168. 
Coupling of 4-(X-2-methoxy-phenyl)-piperidine F or 4-(X-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine H with an N-protected-N-alkyl aminoacid (I) in the presence of activating reagents, such as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (DEAC), 1-hydroxybenzotriazole hydrate (HOBT), 4-methylmorpholine (NMO) forms amide J (Scheme II). The protecting group R is of the urethane type, preferably tert-butyloxycarbonyl which may be removed by the action of an acid. After deprotection, the amide may be reduced to an amine M with a reducing reagent such as lithium aluminum hydride (LAH) or diborane, and subsequently acylated to give compound A. 